Eric SijbrandsEric Sijbrands

Erasmus University Erasmus University Medical CenterMedical CenterRotterdamRotterdam

Mortality from familial Mortality from familial hypercholesterolemia (FH)hypercholesterolemia (FH)

Eric SijbrandsEric Sijbrands

Eric Sijbrands is consultant in internal medicine and head of the lipid clinic of the Erasmus University Medical Center Rotterdam. After he obtained his qualification as medical doctor in 1990, he was given the opportunity to receive his training in internal medicine and to work in scientific research at the Universities of Leiden and Amsterdam. He made a Ph.D. thesis on gene-gene and gene-environment interaction in patients with genetic hyperlipidemia. His present research is focussed on genetic epidemiology of cardiovascular disease (hyperlipidemia, diabetes mellitus, and pharmacogenetics of hypertension).

resumeresume

Learning objectivesLearning objectives

selection on outcome standardization burden of monogenetic disorder genetic heterogeneity gene-environment interaction

Performance objectivesPerformance objectives

understand the clinical consequences of monogenetic disorders

FH - characteristicsFH - characteristics

autosomal dominantautosomal dominant heterozygosity 1:500heterozygosity 1:500 mutations in the LDL receptor mutations in the LDL receptor

gene on chromosome 19gene on chromosome 19 total cholesterol > 8 mmol/Ltotal cholesterol > 8 mmol/L tendon xanthomastendon xanthomas

introductionintroduction

FH - what is already knownFH - what is already known

cardiovascular diseasecardiovascular diseaseat young ageat young age

excess mortalityexcess mortality

population data are lackingpopulation data are lacking

introductionintroduction

Burden of untreated FHBurden of untreated FHintroductionintroduction

analyses of mortality in:

a large pedigree‘free from selection on CVD’

113 small pedigreesreferred to a lipid clinic

Monogenetic disorderMonogenetic disorder

cause disease death

introductionintroduction

Monogenetic disorderMonogenetic disorderintroductionintroduction

additional factors

cause disease death

Natural historyNatural historyintroductionintroduction

Large pedigree: FH-V408MLarge pedigree: FH-V408M

Sijbrands EJG, et al. BMJ 2001;322:1019-23.

introductionintroduction

StandardizationStandardization

SMR = observed / expected deaths

strata per genderstrata per age categorystrata per calendar period

introductionintroduction

SMRSMR

V408M death p.y. SMR (95%CI)

50% 70 6950 1.32 (1.03-1.67) 100% 30 3186 1.59 (1.07-2.26)

large pedigreelarge pedigree

SMRSMRlarge pedigreelarge pedigree

Calendar period

1840 1870 1900 1930 1960 1990

SM

R

0.5

1.0

2.0

3.0

MalesFemales

Kaplan-MeierKaplan-Meierlarge pedigreelarge pedigree

Conclusion 1Conclusion 1

gene-environment

interaction

large pedigreelarge pedigree

113 small pedigrees113 small pedigrees

number

cardiologist 39GP 51insurance 4other 19

total 113

outpatient lipid clinicoutpatient lipid clinic

Sijbrands EJG, et al. Atherosclerosis 1998;136:247-54.

characteristic n=113

male / female 55/58age 48 (20 to 69)xanthomas 66cholesterol 11.04 mmol/L

113 FH patients113 FH patientsoutpatient lipid clinicoutpatient lipid clinic

SMRSMR

age deaths p.y. SMR (95%CI) 1- 19 6 11091 0.45 (0.17-0.98)20- 39 12 10796 1.01 (0.52-1.76)40- 54 43 6317 1.88 (1.36-2.53)55- 69 69 2973 1.76 (1.36-2.22)70- 79 38 688 1.22 (0.87-1.68)80-103 22 184 0.96 (0.60-1.46)

1-103 190 32048 1.34 (1.16-1.55)

outpatient lipid clinicoutpatient lipid clinic

SMRSMR

Age (years)

30 50 70 90

SM

R

0.5

1.0

2.0

3.0

MalesFemales

outpatient lipid clinicoutpatient lipid clinic

Other risk factorsOther risk factors

premature CVD SMR 95% CI

– (51 families) 1.10 0.86-1.34

+ (62 families) 1.62 1.32-1.93

RR+ versus – 1.46 1.09-1.94

outpatient lipid clinicoutpatient lipid clinic

Type of LDLR mutationType of LDLR mutation

characteristic mRNA + mRNA - p(n=24) (n=14)

male, % 58 43 0.4age 50 47 0.4BMI 25.1 25.1 1.0xanthomas, % 42 93 0.001LDL-C 8.86 10.21 0.04HDL-C 1.20 1.04 0.05

outpatient lipid clinicoutpatient lipid clinic

Type of LDLR mutationType of LDLR mutationoutpatient lipid clinicoutpatient lipid clinic

Conclusion 2Conclusion 2

other risk factors for CVD

type of mutation is not relevant

outpatient lipid clinicoutpatient lipid clinic

FH - what these studies addFH - what these studies add

many untreated patients (40%) reach a normal life span

burden of FH depends on time variation in mortality suggests an

interaction between genetic and environmental CVD risk factors

Future ...Future ...

individual risk–molecular diagnosis–additional genes–environmental factors

exact indication for

tailored intervention